In vitro and in vivo studies have suggested therapeutic applications of retinoic acid (RA) for treatment of human neuroblastoma. These studies have indicated that a limitation of treatment may be the outgrowth of neuroblastoma cells that are resistant to the differentiating action of RA. Based upon our in vitro findings that RA-resistant cell variants can be induced into a state of "RA-responsiveness" by increasing intracellular levels of cAMP, we hypothesize that the clinical benefits of RA can be markedly enchanced by combining treatment with modalities that increase intratumor cAMP levels. This hypothesis will be directly tested by evaluating the development and growth of RA-sensitive and RA-resistant neuroblastoma cells in nude mice undergoing various treatment protocols with RA and cAMP-elevating agents. Our previous work has led us to hypothesize a role for modulation of voltage-gated Ca2+ channels by RA inducing differenitation of human neuroblastoma cells. Specific experimental aims for this period are designed to test this hypothesis. In doing so we will address two fundamental questions: Does RA modulate voltage- gated ion channels in human neuroblastoma cells? Is the ability of RA to alter ion channels involved in its differentiation-inducing activity? These investigations will employ the whole cell patch- clamp technique for the electrophysiologic membrane studies and compare the biologic activity of various retinoid derivatives and other "classical" modulators with their effects on channel function. Information gained in this study should provide basic knowledge concerning the roles for ion channels and membrane ion fluxes in regulating cellular growth and differentiation.